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Evaluating the Efficacy of Hydroxychloroquine and Azithromycin to Prevent Hospitalization or Death in Persons With COVID-19

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ClinicalTrials.gov Identifier: NCT04358068
Recruitment Status : Completed
First Posted : April 22, 2020
Last Update Posted : August 3, 2020
Sponsor:
Collaborator:
Teva Pharmaceuticals Industries LTD
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information
First Submitted Date  ICMJE April 20, 2020
First Posted Date  ICMJE April 22, 2020
Last Update Posted Date August 3, 2020
Actual Study Start Date  ICMJE May 1, 2020
Actual Primary Completion Date July 7, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 25, 2020)
Proportion of participants who died from any cause or were hospitalized [ Time Frame: Measured during the 20-day period from and including the day of the first (confirmed) dose of study treatment ]
Hospitalization is defined as requiring at least 24 hours of acute care in a hospital or similar acute care facility, including Emergency Rooms or temporary facilities instituted to address needs during the COVID-19 pandemic. Evaluation at a hospital or similar facility with less than 24 hours of acute care is not considered a hospitalization.
Original Primary Outcome Measures  ICMJE
 (submitted: April 20, 2020)
Proportion of participants who died from any cause or were hospitalized [ Time Frame: Measured during the 21-day period from and including the day of the first (confirmed) dose of study treatment ]
Hospitalization is defined as requiring at least 24 hours of acute care in a hospital or similar acute care facility, including Emergency Rooms or temporary facilities instituted to address needs during the COVID-19 pandemic. Evaluation at a hospital or similar facility with less than 24 hours of acute care is not considered a hospitalization.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 25, 2020)
  • Proportion of participants who died from any cause [ Time Frame: Measured during the 20-day period from and including the day of the first (confirmed) dose of study treatment ]
  • Proportion of participants who died from any cause, or were hospitalized, or had an urgent visit to emergency room or clinic [ Time Frame: Measured during the 20-day period from and including the day of the first (confirmed) dose of study treatment ]
  • Proportion of participants who died from any cause or were hospitalized through the end of follow-up [ Time Frame: Measured during the 20-day period from and including the day of the first (confirmed) dose of study treatment ]
    Hospitalization is defined as requiring at least 24 hours of acute care in a hospital or similar acute care facility, including Emergency Rooms or temporary facilities instituted to address needs during the COVID-19 pandemic. Evaluation at a hospital or similar facility with less than 24 hours of acute care is not considered a hospitalization.
  • Proportion of participants who prematurely discontinue study treatment due to an adverse event [ Time Frame: Measured through Day 7 ]
  • Proportion of participants who had any cardiac adverse events [ Time Frame: Measured from start of study treatment through Day 20 ]
  • Duration of fever [ Time Frame: Measured through Day 20 ]
    Defined as the last day in the participant's daily diary card on which a temperature greater than 100.4°F was recorded or a potentially antipyretic drug, such as acetaminophen or ibuprofen, was taken.
  • Duration of symptoms associated with COVID-19 disease [ Time Frame: Measured through Day 20 ]
    Defined as the last day in the participant's daily diary card on which a moderate or worse symptom was recorded
  • Participant-specific area under the curve (AUC) of the symptom score associated with COVID-19 disease over time [ Time Frame: Measured through Day 20 ]
    Defined as the sum of scores for the targeted symptoms (defined in the protocol) in the participant's daily diary record (each individual symptom is scored from 0 to 3).
  • Time to self-reported return to usual (pre-COVID) health. [ Time Frame: Measured through Day 20 ]
  • SARS-CoV-2 RNA detection status from self-collected nasal and site-collected NP swabs among subset [ Time Frame: Measured at entry, Day 6, and Day 20 ]
  • SARS-CoV-2 RNA level (continuous) from self-collected nasal and site-collected NP swabs among subset [ Time Frame: Measured at entry, Day 6, and Day 20 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: April 20, 2020)
  • Proportion of participants who died from any cause [ Time Frame: Measured during the 21-day period from and including the day of the first (confirmed) dose of study treatment ]
  • Proportion of participants who died from any cause, or were hospitalized, or had an urgent visit to emergency room or clinic [ Time Frame: Measured during the 21-day period from and including the day of the first (confirmed) dose of study treatment ]
  • Proportion of participants who died from any cause or were hospitalized through the end of follow-up [ Time Frame: Measured during the 24-week period from and including the day of the first (confirmed) dose of study treatment ]
    Hospitalization is defined as requiring at least 24 hours of acute care in a hospital or similar acute care facility, including Emergency Rooms or temporary facilities instituted to address needs during the COVID-19 pandemic. Evaluation at a hospital or similar facility with less than 24 hours of acute care is not considered a hospitalization.
  • Proportion of participants who prematurely discontinue study treatment due to an adverse event [ Time Frame: Measured through Day 7 ]
  • Proportion of participants who had any cardiac adverse events [ Time Frame: Measured from start of study treatment through Day 20 ]
  • Duration of fever [ Time Frame: Measured through Day 20 ]
    Defined as the last day in the participant's daily diary card on which a temperature greater than 100.4°F was recorded or a potentially antipyretic drug, such as acetaminophen or ibuprofen, was taken.
  • Duration of symptoms associated with COVID-19 disease [ Time Frame: Measured through Day 20 ]
    Defined as the last day in the participant's daily diary card on which a moderate or worse symptom was recorded
  • Participant-specific area under the curve of total symptom score associated with COVID-19 disease over time [ Time Frame: Measured through Day 20 ]
    Defined as the sum of scores for the targeted symptoms (defined in the protocol) in the participant's daily diary record (each individual symptom is scored from 0 to 3).
  • Time to self-reported return to usual (pre-COVID) health. [ Time Frame: Measured through Day 20 ]
  • SARS-CoV-2 RNA detection status from self-collected nasal and site-collected NP swabs among subset [ Time Frame: Measured at entry, Day 6, and Day 20 ]
  • SARS-CoV-2 RNA level (continuous) from self-collected nasal and site-collected NP swabs among subset [ Time Frame: Measured at entry, Day 6, and Day 20 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Evaluating the Efficacy of Hydroxychloroquine and Azithromycin to Prevent Hospitalization or Death in Persons With COVID-19
Official Title  ICMJE A Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy of Hydroxychloroquine and Azithromycin to Prevent Hospitalization or Death in Persons With COVID-19
Brief Summary The purpose of this study is to evaluate the efficacy of hydroxychloroquine (HCQ) and azithromycin (Azithro) to prevent hospitalization or death in symptomatic adult outpatients with COVID-19 caused by SARS-CoV-2 infection.
Detailed Description

This Phase IIB study will evaluate the efficacy of hydroxychloroquine (HCQ) and azithromycin (Azithro) to prevent hospitalization or death in symptomatic adult outpatients with COVID-19 caused by SARS-CoV-2 infection.

Participants will be randomized 1:1 to receive active/placebo study treatment as follows: HCQ/Placebo 400 mg orally twice a day on Day 0 followed by 200 mg orally twice a day for 6 days, and Azithro/Placebo 500 mg once on Day 0, followed by 250 mg daily for 4 days.

Stratification will be by "high" versus "low" risk of progression to severe COVID-19, where "high risk" is defined as a person age ≥60 years or having at least one of several specified comorbidities.

Participants will receive study treatment for 7 days and will be followed for an additional 13 days. Assessments on a subset of participants will include blood collection, self-collected nasal swabs, and nasopharyngeal swabs.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • COVID-19
  • SARS-CoV 2
Intervention  ICMJE
  • Drug: Hydroxychloroquine (HCQ)
    Administered orally
  • Drug: Azithromycin (Azithro)
    Administered orally
  • Drug: Placebo for Hydroxychloroquine
    Administered orally
  • Drug: Placebo for Azithromycin
    Administered orally
Study Arms  ICMJE
  • Experimental: Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro)

    Hydroxychloroquine 400 mg (administered as two 200 mg capsules) orally twice daily for 2 doses starting on Day 0, followed by 200 mg (administered as one 200 mg capsule) orally twice daily for 12 doses (6 days), PLUS:

    Azithromycin 500 mg (administered as two 250 mg capsules) orally as a single dose on Day 0, followed by 250 mg (administered as one 250 mg capsule) orally once daily for 4 doses (4 days).

    Interventions:
    • Drug: Hydroxychloroquine (HCQ)
    • Drug: Azithromycin (Azithro)
  • Placebo Comparator: Arm B: Placebo for Hydroxychloroquine and Azithromycin

    Placebo for Hydroxychloroquine (administered as two matching placebo capsules) orally twice daily for 2 doses starting on Day 0, followed by Placebo for HCQ (administered as one 200 mg capsule) orally twice daily for 12 doses (6 days), PLUS:

    Placebo for Azithromycin (administered as two matching placebo capsules) orally as a single dose on Day 0, followed by Placebo for Azithromycin (administered as one matching placebo capsule) orally once daily for 4 doses (4 days).

    Interventions:
    • Drug: Placebo for Hydroxychloroquine
    • Drug: Placebo for Azithromycin
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 25, 2020)
20
Original Estimated Enrollment  ICMJE
 (submitted: April 20, 2020)
2000
Actual Study Completion Date  ICMJE July 7, 2020
Actual Primary Completion Date July 7, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Documentation of confirmed active severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection.
  • Experiencing at least one of the following SARS-CoV-2 infection symptoms within 24 hours of screening (symptom(s) must be new or worse compared to pre-COVID-19 health status:

    • Fever (can be subjective) or feeling feverish
    • Cough
    • Shortness of breath or difficulty breathing at rest or with exertion
    • Sore throat
    • Body pain or muscle pain
    • Fatigue
    • Headache
  • Agrees to not participate in another clinical trial for the treatment of COVID-19 or SARS-CoV-2 during the study period up until reaching hospitalization or 20 days, whichever is earliest.
  • Agrees to not obtain study medications outside of the A5395 study.

Exclusion Criteria:

  • Need for hospitalization or immediate medical attention in the clinical opinion of the study investigator.
  • History of or current hospitalization for COVID-19.
  • History of ventricular arrhythmia or using antiarrhythmics within the past 30 days.
  • Personal or family history of Long QT syndrome.
  • History of kidney disease.
  • History of ischemic or structural heart disease.
  • History of hypokalemia or hypomagnesemia or taking potassium supplementation or magnesium supplementation
  • Personal medical history of porphyria, retinopathy, severe hepatic impairment, or glucose-6-phosphate dehydrogenase (G6PD) deficiency.
  • Use of drugs with possible anti-SARS-CoV-2 activity within 30 days prior to study entry, e.g., remdesivir, lopinavir/ritonavir fixed dose combination, ribavirin, chloroquine, hydroxychloroquine, and azithromycin, or participation in a clinical trial involving any of these drugs whether for treatment or prophylaxis.
  • Requirement or expected requirement for a medication that significantly prolongs QT intervals or increases risk for QT prolongation.
  • Loop diuretics are exceptions to above exclusion criterion but these cannot be used within 30 days prior to study entry.
  • Participating in a study where co-enrollment is not allowed.
  • Receipt of a SARS-CoV-2 vaccination prior to study entry.
  • Known allergy/sensitivity or any hypersensitivity to components of HCQ, azithromycin, or their formulation.
  • More than 10 days of any of the following symptoms attributed to the SARS-CoV-2 infection at study entry:

    • Fever (can be subjective) or feeling feverish
    • Cough
    • Shortness of breath or difficulty breathing at rest or with exertion
    • Sore throat
    • Body pain or muscle pain
    • Fatigue
    • Headache
    • Chills
    • Nasal obstruction or congestion
    • Loss of taste or smell
    • Nausea or vomiting
    • Diarrhea
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries Puerto Rico
 
Administrative Information
NCT Number  ICMJE NCT04358068
Other Study ID Numbers  ICMJE ACTG A5395
38720 ( Other Identifier: DAIDS-ES Registry Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Individual participant data that underlie results in the publication, after deidentification.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Time Frame: Beginning 3 months following publication and available throughout period of funding of the AIDS Clinical Trials Group by NIH.
Access Criteria:
  • With whom?

    • Researchers who provide a methodologically sound proposal for use of the data that is approved by the AIDS Clinical Trials Group.
  • For what types of analyses?

    • To achieve aims in the proposal approved by the AIDS Clinical Trials Group.
  • By what mechanism will data be made available?

    • Researchers may submit a request for access to data using the AIDS Clinical Trials Group "Data Request" form at: https://actgnetwork.org/about-actg/templates-and-forms. Researchers of approved proposals will need to sign an AIDS Clinical Trials Group Data Use Agreement before receiving the data.
Responsible Party National Institute of Allergy and Infectious Diseases (NIAID)
Study Sponsor  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators  ICMJE Teva Pharmaceuticals Industries LTD
Investigators  ICMJE
Study Chair: Davey Smith, MD University of California, San Diego
PRS Account National Institute of Allergy and Infectious Diseases (NIAID)
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP